Abstracts Vol. 1 [International Conference on AIDS (11th: 1996: Vancouver, Canada)]

Tu.B.2276 - Tu.B.2280

Tuesday July 9, 1996

Results: Results ar e is followed (Mear+SEFM):

BPO (prniol/kg/min)
BEO (pmol/kg/niin)
LPO (nmol/mi)
MDA (rnmol/rml)
Vii C (umrol/I)
a-tocopherol (ug/dl)
B carotene (ug/dl)

HIV+AIDS
9.2~+1.4
30.6~4.4
31.3+~5.9
0.29+0.03
35.6~+2.5
970+51
12.23+2.27

Control
6. I ~0.6*
1I 1.4~0.6*
4.5~0.8*
0.24~0.06
75.7~4.3*
1146 ~112*
20.46~2.22*

PValue
P<0.05
P<0.05
P<0.05
NS
P<0.005
P<0.005
P<0.05

Conclusion: HIV infected patients have a higher oxidative stress and lower antioxidant vitamin status when conpared to controls.This oxidative stress is similar between HIV asymptomatics and AIDiS. It remains to be determined whether supplementation of antioxidant
vitamins will reduce this oxidative stress.
Dr Johane P Allard -The Toronto Hospital, General Division 200 Elizabeth Street - 9 EN
217A,Toronto, Ontario, ( inada M5G2C'
Telephone: (4 16) 34'0 5 159 Fax [phone]
Tu.B.2276
PHASE I OPEN LABEL STUDY OF THE SAFETY AND POTENTIAL EFFICACY OF
LIGLA IN ADVANCED HIV INFECTION
Schlech Walter F* Conway B", Haldane H*, Hyndman S*, Meagher N*, Currie M*, Singer
J +,Winther M'i. *tDepartment of Medicine, Dalhousie University, Halifax, NS; **St. Paul's
Hospital,Vancouver B(; ' "Scotia Pharmaceuticals Inc., Kentville, NS; +The Canadian HIV
Clinical Trials Network.
Objective: To determine the safety of intravenous administration of LiGLA in the treatment
of advanced HIV infection.
Methods: Lithiumi gamma-inolenate acid (LiGLA) activity kills HIV-infected cells in vitro. A
phase I, dose escalating study of the safety and toxicity of intravenously administered LiGLA
was cari ed out in 12 patients with dvnced HIV infection. LiGLA was administered daily
intravenously through a central catheter for 14 15 days at a median dose of 46 grams.
Hermatologic and bioclserrical profiles and clinical symptoms were monitored to assess toxicity. Hematologic and virologic assays were carried out including quantitative p24, quantitative HIV PCR RNA, CD4 counts and beta-2 microglobulin assays to assess the potential in
vivo antiviral effect of LiG A. A 35 question modified MOS-HIV quality of life (Q.O.L.) measure was carried out at start and end of study
Results: Ten male and two female patients (mean age = 40) were enrolled.The mean CD4
cell count at start of study was 60 (range 15-221); the mean CD4 at day 30 was 62 (range
7-22 1). 6/12 patients were taking other antiretrovirals (I patient 3TC + AZT 2 patients
DDI, 3 patients 3TC). No change in antiretroviral therapy had been made in the two
months prior to study 9/12 patients had mild phlebitis from the PICC line or port-a-cath
site. A significant decrease in hermaglobin accompanied by asymptomatic hemaglobinuria
occurred in most patiernts (mean hemnaglobin at entry 128.5, mean hemaglobin at day 30
I 19.2).The haptoglobin decreased as expected in most patients. Side effects included gastrointestirnal disturbance (I 0/I12 patients), fatigue (4/12 patients), headache (8/12 patients);
no patients were discontinued from study because of side effects.The mean plasma viral
copies/cu/mm at entr y was 122,290 (range 8,228-505,282). Lower copy numbers were
associated with a negative p24 status. A transient decrease in plasma HIV PCR-RNA was
noted in three patients at study midpoint. Q.O.L. scores remained stable pre and post study.
Conclusions: Despite freqrent side effects, LiGLA can be safely administered intravenously
to patients with advanced HIV infection.VWhile a transient decrease in plasma viral load was
seen in several patients the in vivo antiviral efficacy of LiGLA remains to be determined by
randomized clinical trials.
Walter F. Schlech III, Room 50 I 4 ACC,Victoria General Hospital I 278 Tower Road, Halifax,
N.S., Canada B313 3Y9
Tu.B.2277
A RANDOMISED TRIAL TO EVALUATE EFFECTIVENESS OF CAESAREAN SECTION
IN THE PREVENTION OF HIV VERTICAL TRANSMISSION.
Bazin Brigitte*, Mandelbrot., Parazzini F.", the international "MOD Trial" group'***.
*Inserm SC I 0.Villejuil, Fr ance; "Mario Negri Institute, Milan, Italy; **MRC, London,
England
Objectives: A large proportion of mother-to-child HIV transmission (MCT) is thought to
occur during labor and delivery However observational studies show conflicting results
regarding the effect of mode of delivery (MOD) upon MCT.
The international MOD Trial group initiated anr international, multicentre, randomised trial to
(1) evaluate the effectiveness of elective caesarean section in decreasing MCT, (2) determine the impact of MOD on maternal morbidity and HIV progression.
Method:TFo detect a 2--fold reduction in transmission risk (12% to 6%), 1500 pregnant
women will be enrolled, taking into account differences in use of Zidovudine among trial
sites and the number- of women who will not have the mode of delivery to which they
have been randomised.
At 36 weeks of amenorrhea (or later) women who have signed informed consent and do
not have a clinical indication for a caesarean section delivery are randomised in a 1:1 ratio
to either elective caesareran section delivery (to take place at 38 weeks) or vaginal delivery
Women will be assessed at 6 weeks post partumn and at 6 months after delivery (clinical,
hematological and immunological information). Maternal morbidity will be compared
between the 2 groups.
Children will be assessed at 6 weeks of age, I 2 weeks and every 3 months until I 8 months
of age. Infant HIV infection status in the 2 groups is the primary endpoint.
Trial setting:The MOD Frial is ongoing. It started first in Italy in 1993, followed by France
and South Africa in Jurne I995. Enrollment is beginning in UK, Switzerland, Spain and
Sweden. About 250 women have been enrolled to date.
B3Bazin, lnser SC i 0, 16 avenue RV. Couturier 94807 Villejuif Cedex FRANCE Telephone:
33- I-45 59 5! 57 Es's 33-1I-45 59 51I 80. emnail: b.bazinL'avjfinserm.fr

Tu.B.2278
FLUPIRTINE PROTECTS BOTH NEURONAL CELLS AND LYMPHOCYTES AGAINST
INDUCED APOPTOSIS IN VITRO: IMPLICATIONS FOR TREATMENT OF AIDS
PATIENTS
MlleriW rnerEG*, Dobmeyer JM**, DobmeyerTS**,. Pergande G+, Perovic S*, Leuck J*,
Rossol R*. *Institut fIr P',ysiologische Chemie, Universitit, Mainz, Germany: *Dnritte
Medizinische KlInik, Unlriversitit, Frankfurt, Germany; +ASTA Medica AG, Frankfurt, Germany
Objective: It has been argued thatT-cell depletion and neuronal death in HIV-I infection is
due to apoptosis. A drug which prevents this form of cell death was hitherto unknown.
Drug: In the present study we demonstrate that flupirtine [trademark Katadolon~], an
already clinically used, centrally acting, non-opiate analgesic agent, prctects lymphocytes and
neurons against induced apoptosis.
Methods: Human lymphocytes and rat cortical neurons have been used. As inducer of
apoptosis in lymphocytes we have used the hypoxantine/xanthine oidase system and lonomycin. Neurons were induced to apoptosis by gpl120.
Results: Flupirtine does not affect spontaneous apoptosis in human lymphocyvtes in vitro.
However, induced apoptosis in peripheral blood mononuclear cells from healthy individuals
and HIV- I infected patients was reduced to approximately 50% after in vitro preincubatron
with flupirtine at concentrations between 0. I and 10 pg/ml. Furthermore we could demonstrate that the anti-apoptotic effect of flupirtine was restricted to CD3+ lymphocytes and
in particular to CD4+ cells. Ionomycin was used as an alternative inducer of apoptosis to
exclude a protective effect of flupirtine on the induction of apoptosis due to potential
properties as radical scavenger Flupirtine markedly decreased ionomycin-induced apoptosis
to a degree as observed in the experiments with hypoxantine/xanthine oxidase. Flupirtine
protects rat cortical neurons against HIV-gp I 20 induced apoptotic cell death; the drug was
active at concentrations between I and 10 pg/ml.
Conclusion:The potential of flupirtine to selectively reduce induced apoptosis without
influencing spontaneous apoptosis may qualify this compound as a potential drug in the
therapy of HIV- I infected patients.This conclusion is supported by pharmacokinetic data
which revealed that after a single oral application of 200 mg of flupirtine a plasma level of
I pg/ml is reached for I2 h in humans; this concentration was found in the present study to
act anti-apoptotically in vitro both in the induced lymphocyte- and the neuronal cell system.
WE.G. Muller Institut fur Physiologische Chemie, Universitat, Duesbergweg. 6, 55099 Mainz,
GERMANYTelephone: [phone] Fax: [phone]
Tu.B.2279
GM-CSF IN HIV RELATED LEUKOPENIA: EFFICACY AND TOLERABILITY OF THREE
MONTHS THERAPY ON 50 PATIENTS
Barbarini, G., Garavelli, G., Grisorio, B.*, Barbaro, G.", Giangregorio, F.~. Division of Infectious
and Tropical Diseases I.R.C.C.S, S. Matteo, University of Pavia Multicenter Group: *Foggia.
oRoma, ~Pavia.
Objective:The purpose of our study was to optimize the dose, schedule and timing of GMCSF administration in HIV positive patients presenting HIV-related leukopenia.
Subjects and Methods: Since April 1995, 100 consecutive asymptomatic, leukopenic HIV
positive patients (WB Cells count less than 3000) not submitted to any mielosuppressive
chemotherapy were randomized into two groups of 50:
Group A) No treatment with any stimulating factor group.
Group B) Treatment with GM-CSF at the dosage of 300 mcg daily S.C. for 5 days followed
by two weekly doses of 150 mcg. for 10 weeks.
Results: At the end of the therapy we observed an increase of WB Cells count >20% in 34
treated patients, > 10% in I I and no increase, but no decrease, in 5. In the control group
(not treated subjects) we demonstrated an increase of WBC >10% only in I subject, no
increase and decrease in 43 and a decrease in 6.We observed Flu-like symptoms in 42
treated patients during the first week of therapy; generally these symptoms abated with the
reduction of the dosage. No one therapy was interrupted.
Discussion: Our controlled study demonstrated a significant larger increase (p<0.0 I) in
leukocytes, neutrophils and lymphocites during the whole treatment period, than in controls.We didn't observe any effect on platelets levels; side effects (flu-like symptoms) were
dosage-related.
Giorgio Barbarini, Clinic Infectious and Tropical Diseases IRCCS, S. Matteo University of
Pavia 27100 Pavia (Italy) Telephone: [phone] Fax [phone]
Tu.B.2280
STRATEGIES FOR THE INHIBITION OF SEXUAL TRANSMISSION BY TOPICAL
ANTIVIRAL AGENTS
O'ConnorTJ, Jeffries DJ. Department of Virology The Medical College of St Bartholomews
Hospital, London
A number of substances have been identified which have either a specific virucidal effect on
HIV, or prevent infection of cells in vitro. Key facts are lacking in our knowledge of the efficacy and toxicity of candidate agents and this is a handicap in the planning of clinical trials.
Some clinical studies suggest the possibility that topical agents may fircilitate rather than
inhibit HIV transmission, which may be due to damage to epithelial tissue and an increase in
genital ulceration. Factors found in semen and the female genital environment may mediate
the infectivity of cell free and cell associated HIV together with their effect on the activity of
virucides. Semen and cervical secretions were assessed for their ability to inhibit HIV. Only
semen was found to have any significant activity against HIV with a se ectivity index (SI) of
approximately 40.The effect of low pH. normally present in the female genital tract, on HIV
viability was also examined by direct exposure of virus to a range of pH's and subsequent
assessment for viral viability HIV appears to be more acid stable than previously reported
with no substantial reduction in infectivity occurring until pH levels are reduced below 4.5.
The virucidal activity of a number of commonly used topical spermicides was assessed
against cell-free and cell-associated virus using previously established and newly modified
assay systems. Although nonoxynol-9 and other surfactants inactivated HIV at low concentrations, the cytotoxic effects on the cell lines used resulted in low selectivity sedices; none
having a SI greater than six. Other classes of agents such as the polysaccharides e.g. dextnn
sulphate and fucoidas or lonophores like gramucidrn had higher SI's (200. 200 & 50

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